Methamphetamine is a powerful psychostimulant with considerable abuse potential. Currently, it is one of the most popular of the "Club Drugs." As with cocaine, methamphetamine appears to be most amenable to treatment via behavioral interventions. However, recent advances in our understanding of the pharmacology of the psychostimulants and human neuroanatomy have increased the likelihood of finding a pharmacotherapeutic agent that will decrease methamphetamine use without producing unacceptable side-effect profiles. It will be important to assess these new pharmacotherapies in an ecologically valid model. Furthermore, methamphetamine, like most drugs, is rarely taken by itself. Instead, it is frequently one of several drugs included in a polysubstance panoply. An ecologically valid model of methamphetamine self-administration using human volunteers will be needed to determine how this pattern of polysubstance use influences the subjective, physiological and reinforcing potential of methamphetamine. This proposal describes a plan to modify and combine two human self-administration models that have been validated with other drugs of abuse. The models have been shown to be sensitive to both pharmacological and environmental manipulations. In brief, the new model will allow for the examination of the variable of interest (pharmacological or environmental) on methamphetamine self-administration under three different conditions each of which occasions a different degree of self-administration (low, medium and high). It will also provide a platform from which information on the subjective and physiological effects of methamphetamine, alone or in combination with other drugs, can be measured. It is our belief that such an approach represents a pragmatic use of resources. Studies using laboratory models of human drug use can inform subsequent clinical trials and help to focus them on those variables which are likely to be important.